1. Field of the Invention
This invention relates to a novel class of heterocyclic compounds useful for selectively inhibiting trypsin-like enzymes, selectively inhibiting chymotrypsin-like enzymes, selectively inhibiting elastase or for generally inhibiting serine proteases of all classes. This invention also relates to a method of controlling blood coagulation, tumor invasiveness and treating inflammation in patients using the novel compounds of the present invention. We have found that substituted isocoumarins are potent inhibitors of blood coagulation enzymes, complement enzymes, tryptases, kallikreins, plasmin and elastase, therefore they are useful as anticoagulants, anti-inflammatory and anti-tumor agents.
2. Description of the Related Art
Serine proteases play critical roles in several physiological processes such as digestion, blood coagulation, complement activation, fibrinolysis, and reproduction. Serine proteases are not only a physiological necessity, but also a potential hazard if they are not controlled. Blood coagulation serine proteases are responsible for vascular clotting, cerebral infarction, and cornary infarction. Plasmin is involved in tumor invasiveness, tissue remodeling, and clot dissociation. Uncontrolled proteolysis by other serine proteases such as elastases may cause pancreatitis, emphysema, rheumatoid arthritis, inflammation and adult respiratory distress syndrome. Accordingly, specific and selective inhibitors of these proteases should be potent anticoagulants, anti-inflammatory agents and anti-tumor agents useful in the treatment of protease-releated diseases (Powers and Harper, in Proteinase Inhibitors, Barrett and Salvesen, eds., Elsevier, 1986, pp 55-152, incorporated herein by reference). In vitro proteolysis by trypsin, chymotrypsin or the elastase family is a serious problem in the production, purification, isolation, transport or storage of peptides and proteins.